Effects of procainamide hydroxylamine on generation of reactive oxygen species by macrophages and production of cytokines.
A series of experiments was conducted to examine the effects of the N-oxidized metabolite of procainamide, procainamide hydroxylamine (PAHA), on reactive oxygen species (ROS) production by macrophages in vitro, as well as on the release of the cytokine interleukin-1 (IL-1). Results with PAHA were compared with those from the parent compound, procainamide, and in some cases with other procainamide metabolites such as N-acetylprocainamide or nitrosoprocainamide. The effects of PAHA on ROS production by mouse and rat macrophages were complex, resulting in both stimulatory and inhibitory activity depending upon the PAHA concentration and whether macrophages were resting or elicited. The primary effect of PAHA appeared to be a stimulation of ROS production. Monocytes pretreated with PAHA (20 microM) depressed the responsiveness of lymphocytes in co-culture to a T-cell mitogen (conconavalin A) but not a B-cell mitogen (lipopolysaccharide). This effect was inhibited when monocyte pretreatment with PAHA was accompanied by the antioxidants, catalase or superoxide dismutase. IL-1 production by rat adherent splenocytes was unaffected by PAHA in concentrations that were not cytotoxic. These observations suggest that the oxidative metabolism of procainamide to PAHA may result in enhanced production of ROS by macrophages contributing its toxicity to lymphocytes.
Adams
L E
LE
Department of Medicine, University of Cincinnati Medical Center, OH 45267.
Roberts
S M
SM
Carter
J M
JM
Wheeler
J F
JF
Zimmer
H W
HW
Donovan-Brand
R J
RJ
Hess
E V
EV
D000818:Animals; D005609:Free Radicals; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000096:biosynthesis; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D010100:Oxygen / Q000378:metabolism; D011342:Procainamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew
D005609:Free Radicals; D007375:Interleukin-1; C051948:procainamide 4-hydroxylamine; D011342:Procainamide; D010100:Oxygen